Both coinfections of Penicillium marneffei and Cryptococcus neoformans in AIDS patient

Opportunistic infections can cause significant morbidity and mortality in AIDS patients [1]. Tuberculosis (TB), cryptococcosis and penicilliosis are the most common opportunistic infections in HIV/AIDS individuals in Southeast Asia [2]. Coinfection with Cryptococcus neoformans and Penicillium marneffei has not been properly understood and is a challenge in clinics. A 40-year-old woman, who was a farmer, was admitted to hospital in May 2010 for interrupted fever for 3 months, multiple umbilicated papules, nodules, with necrosis and crusts on her face, trunk, scalp and extremities for 2 months (Fig. 1a). The patient had lost 15 kg in weight in 1 year, and she had a history of TB, thrombocytopenia and recurrent herpes zoster during the past 3 years. Her HIV antibodies were confirmed positive on 8 January 2010 and the baseline CD4+ cell count was 20 cells/μl. Investigation revealed platelet (PLT) was 8 × 109 cells/l, splenomegaly and histopathological examination of skin papule showed the presence of lymphocytic infiltration and other inflammatory cells (Fig. S1A, https://links.lww.com/QAD/B141). Periodic acid Schiff stain revealed yeast cells (Fig. S1B, https://links.lww.com/QAD/B141) and papular culture was positive for P. marneffei (Fig. S1C, https://links.lww.com/QAD/B141). Lumbar puncture revealed cerebrospinal fluid (CSF) opening pressure of 330 mmH2O and CSF India ink stain for C. neoformans was positive (Fig. S1D, https://links.lww.com/QAD/B141). CSF culture grew C. neoformans and urease test for C. neoformans was positive.Fig. 1: Clinical features of face.(a) Multiple umbilicated papules and nodules with necrosis and crusts appeared on the patients face at the time of first presentation. (b) Reduction in multiple umbilicated papules with necrosis and crusts after 2 months of treatment. (c) The umbilicated papules reduced in size and number, no crusta and no necrosis after 1 year of treatment. (d) No signs of lesion on the patient's face upon follow-up in 2015, 5 years later.HAART was given to the patient. Intravenous amphotericin B was administered and the dose was gradually increased to 25 mg/day, which continued for 4 months. Afterwards, the patient was treated with oral itraconazole 400 mg/day for 8 months. The CSF analysis on the 14th day showed opening pressure of 210 mmH2O, and CSF India ink stain was positive for Cryptococcus. After 2 months of treatment, investigation showed that the PLT was 103 × 109 cells/l, reduction in size and number of umbilicated papules (Fig. 1b). The CSF analysis showed decreased opening pressure and CSF India ink stain was still positive. Five months later, review of investigations revealed PLT was 129 × 109/l and CD4+ cell count was 84 cells/μl. After 1 year, the follow-up demonstrated that the skin lesions decreased markedly in size and number (Fig. 1c), the CD4+ cell count increased to 140 cells/μl and CSF India ink stain still remained positive. The other lab investigations returned to normal. Oral itraconazole therapy of 400 mg/day was extended for further 6 months due to positive India ink stain and persisting cutaneous lesions. In May 2015, patient's CSF India ink stain became negative, CSF examination and blood culture was negative. The CD4+ cell count in patient increased to 200 cells/μl in 2014 and to 240 cells/μl in 2015. The umbilicated papules on face disappeared and only atrophic scars were left behind (Fig. 1d). The patient gained 5 kg in weight and the patient continued her HAART therapy until the reporting day. The current report is the successful treatment of a rare case of two fatal fungal coinfections with extremely high intracranial pressure, although without headache, vomiting and fever, of which there is not a clinical guideline currently. C. neoformans inhaled through the respiratory tract always leads to pneumonia, and it further progresses into meningitis in case of suppressed immune function. The early clinical manifestations of C. neoformans infection include headache, fever, nausea and vomiting. P. marneffei is also inhaled through the respiratory tract, and cough, expectoration, pectoralgia, weight loss, hepatosplenomegaly and lymphadenopathy are common clinical manifestations [3]. The umbilicated necrotic papules are classical mucocutaneous manifestations of C. neoformans and P. marneffei. Patients resembling identical clinical manifestations to our case with umbilicated necrotic papules and fever are recommended to go for fungal, blood and CSF examinations. It is reported that the bone marrow aspirates and lymph node biopsy reveals the highest rate of diagnosis, followed by skin biopsy and blood culture [4]. Therefore, it is important to clarify the diagnosis of opportunistic infections by various test methods, such as clinical identification of umbilicated necrotic papules, papular culture, corresponding lower CD4+ and history of infectious disease. After clear diagnosis, treatment given to this patient included intravenous 25 mg/day of Amphotericin B for 4 months and oral 400 mg/day of Itraconazole for 14 months. Antifungal treatment was longer than the guideline [5,6]. This study suggests that HIV/AIDS patients with penicilliosis and cryptococcosis coinfections may need longer treatment duration until the fungal tests become normal and lesions subside. In addition, this patient was identified to be HIV-positive because of long-term low PLT, which indicates PLT is associated with coinfections in HIV/AIDS patients. Acknowledgements We are grateful to the patient, doctors and study nurses associated with the participating study. This work was supported by the National Natural Science Foundation of China (81371812 and 81560325); the Fund for Innovative Talent of Science and Technology in University of Henan Province, China (17HASTIT049); the Medical Leadership Foundation of Health and Family Planning Commission of Yunnan Province, China (L-201613); the Science and Technology Innovation Team of Sexually Transmitted Diseases of Kunming Medical University (CXTD201609)]; and the Science and Technology Department of Yunnan Province-Kunming Medical University Applied Basic Research Joint Special Foundation. Conflicts of interest There are no conflicts of interest.